1. Field of the Invention
The present invention relates to a novel antifungal molecule 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1xe2x80x2-methylethyl pentanoate of formula (I). It particularly relates to a novel antifungal lead molecule isolated from a plant Datura metel.
The main utility of the invention is to provide a new lead molecule for development of new drugs for treating diseases caused by pathogenic fungi.
2. Background of the Technology
The incidence and mortality due to mycotic infections has been observed to be on the rise in the past decade (Saral, R., 1991, Rev. Inf. Dis. 13, 487-492., Koll, B. S. and Brown, A. E. 1993, Clin. Inf. Dis. 17, S-322-S-326). Infections induced by these species are increasingly recognized as emerging threat to the public health. In immuno-compromised host, the infections by Aspergillus, Candida, Histoplasma etc. become invasive and disseminate from primary site of infection to other parts of the body including gut, kidney, brain etc. Invasive aspergillosis is reported to be associated with a mortality rate of 55% (Denning, D. W. and Stevens, D. A., 1990, Rev. Inf. Dis., 12, 1147-1201). Mortality due to Aspergillus infection in bone marrow transplant recipients was observed to be as high as 80% despite appropriate chemotherapy (Meyer, J. D., 1990, Semin. Oncol. 17 (suppl. 6), 10-13). Cerebral aspergillosis presents the symptoms of acute meningitis and is always fatal. Candida species are commensal organisms of human mucocutaneous surface. However, in immunocompromised host, Candida may progress to become opportunistic potential pathogen. It may be transmitted by contact to other immuno-compromised patients as a nosocomial pathogen.
It is, therefore, important to diagnose and treat these fungal infections at early stage to prevent irreversible damage. For the treatment of mycoses, several compounds belonging to azoles, polyenes and other groups of chemicals have been described in the literature. But all of these compounds have their own limitations.
Polyenes are among the oldest and most frequently prescribed antifungal agents. Amphotericin B is an important polyene drug which has been found to have a broad range activity against fungi, but its therapeutic doses are frequently associated with severe chills, fever, vomiting, life threatening hypotension and respiratory distress. Amphotericin B produces renal dysfunction (Allende, M. C., Lee, J. W., Francis, P., Garrett, K., Dollenberg, H., Berenguer, J., Lyman, C. A., Pizzo, P. A. and Walsh, T. J. 1994, Antimicrob. Agents and Chemother. 38, 518-522) and necessity of its intravenous administration is its major limitation (Stevens, D. A. and Lee, J. Y., 1997, Arch. Int. Med., 57, 1857-1862). In addition to its adverse effects, Amphotericin B resistance in fungal species has been reported (Gokhale, P. C., Kshirsagar, N. A. and Pandya, S. K., 1993, Current Science 65(6), 448-454, Forthergill, A. W. and McGough, D. A., 1995, Clin. Microbiol. Procedure Handbook, In Vitro susceptibility Testing of Yeast, 5.15.1-5.15.15).
Nystatin is another important drug, however, the development of resistance and its dose limited toxicity make this drug also less useful (Forthergill A. W. and McGough A. W., 1995, Clin. Microbiol. Procedure Handbook, In Vitro susceptibility Testing of Yeasts, 5.15.1-5.15.15).
New azole antifungals such as ketoconazole, fluconazole and itraconazole provided the hope that these compounds might be useful to prevent or treat fungal infections. However, their liver toxicity, hypoglycemic nature and development of resistant strains of fungi did not keep this hope alive for longer period (Denning, D. W. Tucker, R. M., Hanson, L. H., Hamilton, J. R. and Stevens, D. A., 1989, Arch. Int. Med., 149, 2301-2308). The azoles are reported to decrease the secretion of stomach acid and thereby reducing the absorption of drug itself and other important biomolecules. These effects may cause severe drop in body glucose to a level which may be life threatening. Resistance against the azole derivatives also has been reported in fungi (Forthergill A. W. and McGough A. W., 1995, Clin. Microbiol. Procedure Handbook, In Vitro susceptibility Testing of Yeasts, 5.15.1-5.15.14).
Currently available antifungal drugs are not sufficiently broad in their spectrum and not consistently effective against fungi including Aspergilli. These drugs are either toxic or immunosuppressive in nature. Further, the development of resistance in fungi to most of available drugs has also been reported.
It is evident from the above that need exists for development of new antifungal drugs which obviate the drawbacks listed above. The novelty of the present invention is to provide a process for isolation and characterization of a novel antifungal lead molecule from Datura metel, which is many fold less cytotoxic as compared to standard antifungal drug such as amphotericin B.
The main object of the present invention is to provide a novel antifungal lead compound 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1xe2x80x2-methylethyl pentanoate for developing new drugs against the pathogenic fungi.
Another object of the invention is to provide the process for isolation of the novel antifungal lead molecule 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1xe2x80x2-methylethyl pentanoate from a plant Datura metel. 
Still another object of the present invention is to provide a method for testing the novel compound 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1xe2x80x2-methylethyl pentanoate as an antifungal agent.
Yet another object of the invention is to provide usage of the novel compound 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1xe2x80x2-methylethyl pentanoate as an antifungal agent.
Still yet another object is to provide a novel antifungal lead molecule 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1xe2x80x2-methylethyl pentanoate which is 57.8 times less cytotoxic than the standard antifungal drug such as Amphotericin B.
The present invention is directed to a novel antifungal compound 2-(3,4 dimethyl-2,5-dihydro-1H-pyrrole-2-yl)-1xe2x80x2-methylethyl pentanoate of the formula (1) as given below. The compound has antifungal properties and is several times less cytotoxic as compared to the standard antifungal drugs. This compound may be useful for controlling systemic and superficial fungal infections in humans with fewer toxic effects. This compound has been isolated from an easily available plant Datura metel.